Studies on the mechanism of the antifibrinolytic action of tranexamic acid

The effect of the antifibrinolytic agent tranexamic acid on the solubilization of 125I-labeled fibrin by plasmin or by mixtures of plasminogen and plasminogen activator (tissue activator or urokinase) was studied. The time required to solubilize half of the radioactivity (S50) decreased curvilinearly with the logarithm of the concentration of plasmin or plasminogen. Tranexamic acid caused a concentration-dependent retardation of fibrinolysis. When corresponding S50 values were converted to apparent concentrations of plasmin or plasminogen in the absence of tranexamic acid, sigmoidal relationships were obtained between the apparent plasmin(ogen) concentration and the logarithm of the concentration of tranexamic acid. When tissue activator (with a high affinity for fibrin) was used, the shape of these curves was compatible with single association reactions between plasminogen and tranexamic acid. A 50% decrease of the apparent plasminogen concentration was obtained at 1.2 μM tranexamic acid for native plasminogen (Glu-plasminogen) and 2.3 μM for proteolytically degraded plasminogen (Lys-plasminogen). The dissociation constants of the interaction between tranexamic acid and the high affinity lysine-binding site of Glu-plasminogen or Lys-plasminogen have previously been estimated at 1.1 and 2.2 μM, respectively. Direct measurements of the binding of 125I-labeled plasminogen to fibrin clots revealed that tranexamic acid displaced plasminogen from the fibrin surface; a 50% displacement was obtained at 1.3 μM tranexamic acid for Glu-plasminogen and 5.0 μM for Lys-plasminogen. These observations are compatible with the interpretation that saturation of the high affinity lysine-binding site of plasminogen with tranexamic acid results in its displacement from the fibrin surface and abolishes its activation by fibrin-bound plasminogen activator. When native or degraded plasminogen was activated with urokinase (with a low affinity for fibrin), tranexamic acid also caused a concentration-dependent retardation of fibrinolysis but of a much more complex nature. Saturation of the high affinity lysine-binding site in plasminogen with tranexamic acid had no significant influence on the solubilization rate of fibrin, indicating that binding of plasminogen to fibrin is of little importance for its activation by urokinase. At higher tranexamic acid concentrations an enhancement of Glu-plasminogen activation was observed, followed by interference of tranexamic acid with fibrinolysis by plasmin. These effects have already been described previously. Tranexamic acid caused a concentration-dependent retardation of fibrinolysis by plasmin; a 50% reduction of the apparent plasmin concentration was obtained at 45 μM tranexamic acid.